The Role of Estrogen in the Development of Age-Related Cognitive Impairment and Dementia

During and after menopause,
many women report impairments
in cognitive functioning.
One of the most controversial issues in
medicine today is the decision to
prescribe hormone therapy for women
as a way to mitigate the physical and
cognitive symptoms of menopause.
There is some evidence that estrogen
therapy (ET) results in the maintenance
of a premenopausal level of cognitive
functioning1-4 and may reduce the risk
of Alzheimer disease (AD).5-8 With
many in the baby boom generation now
well into menopause, this issue will be
of increasing importance in the coming
years.

Contrasting results

Studies examining the difference in
hormone levels in postmenopausal
women with and without AD yield
contrasting results. While one study
found women with AD to have significantly
lower estradiol levels than healthy controls,9 suggesting a possible
relationship between estrogen and
the risk of AD, another study found no
significant difference in estradiol levels
between these 2 groups and no correlation
between cognitive performance
and hormone levels.10

Women appear to be at higher risk
for AD than men, particularly if they
carry the APOE4 allele.11 Furthermore,
certain estrogen receptor 1 polymorphisms
appear to be associated with
the risk of cognitive impairment.12 Estrogen reduces neuronal generation
of β-amyloid peptides, which may cause
a delay in the onset of AD.13

There is considerable epidemiologic
evidence from both prospective
and case-control studies that estrogen
use in postmenopausal women may
decrease the risk of the development
and/or expression of AD,5-8,14,15 with an
overall odds ratio of 0.66,16 but not all
studies have found this.17 ET alone may
improve cognitive functioning in female
AD patients.18 However, other trials of
estrogen alone as a therapy for mild to
moderate AD have had equivocal results, showing no significant effect
on cognitive measures of long-term
progression,19-21 suggesting that estrogen
alone cannot significantly prevent
progression of an already established
disease.

ET may, however, be helpful in
cognitive decline resulting from normal
aging, as opposed to reversing or
preventing established AD pathology
specifically. Some of the most consistent
evidence for a direct effect of
estrogen on cognitive function is from
studies of surgically menopausal
women.

Sherwin22 studied women after total
abdominal hysterectomy/bilateral salpingo-oophorectomy with random
assignment to estrogen or placebo for
3 months and found that the treated
group showed preservation of verbal
memory, while the placebo group
showed a significant decline. These data
were confirmed in a study showing that,
for 3 months after this surgery, estrogen-
treated women showed either
improvement in or preservation of
verbal learning and memory performance,
while placebo-treated women
showed a decline.23

In a naturalistic study, women who
received estrogen after surgical menopause
had better preserved verbal memory
and constructional ability than
women not receiving estrogen.24 In addition,
2 studies showed that ET specifically
improves attentional functions,
compared with placebo treatment.4,25